POS0249 FIBROBLAST ACTIVATION PROTEIN AS A LINK BETWEEN INFLAMMATION AND VASCULAR REMODELING IN GIANT CELL ARTERITIS
Authors: S. Xu, W. F. Jiemy, A. Boots, Y. Van Sleen, K. Van der Geest, P. Heeringa, E. Brouwer, M. Sandovici
Journal: Annals of the Rheumatic Diseases (2022)

Background Giant cell arteritis (GCA) can present with serious complications such as blindness, stroke and aortic aneurysm that are related to both inflammation and remodeling of the vessel wall. GCA frequently overlaps with polymyalgia rheumatica (PMR). The pathogenesis of GCA starts in the adventitia where fibroblasts are the major stromal cell population. A preliminary study [1] reported the migration of adventitial fibroblasts to the intima, contributing to intimal hyperplasia in GCA. Fibroblast activation protein (FAP) is a non-classical serine protease which can be present in both a membrane-bound form and a soluble form and has been demonstrated to promote inflammation and fibrosis in coronary artery disease and rheumatoid arthritis [2-3] . We hypothesize that FAP is involved in GCA vasculopathy due to its pro-inflammatory and pro-fibrotic effects. Objectives As a first step to unravel the contribution of FAP to the vasculopathy in GCA, we determined FAP plasma levels and FAP protein expression at the site of vascular inflammation in GCA. Methods In our prospective cohort of GCA, PMR and healthy elderly (GPS), we measured the plasma FAP levels with ELISA in new-onset, treatment-naïve GCA (N=62), and PMR (N=63) patients and 42 age-matched healthy controls (HC). In addition, we measured the plasma FAP levels at follow-up (3-months, 1-year, 1.5-year and treatment-free remission (TFR)). Temporal artery biopsies (TAB) from treatment-naïve GCA patients (n=9) and non-GCA patients (n=9), aorta samples from GCA-related aneurysm (n=9) and atherosclerosis (n=11) were stained for FAP using immunohistochemistry. Immunofluorescence staining for CD90, CD68, αSMA and FAP was performed to detect FAP expression in fibroblasts, macrophages and vascular smooth muscle cells (VSMC), respectively. Results Baseline plasma FAP levels were significantly lower in GCA patients (52.72±2.93 ng/ml) than in PMR patients (66.42±2.86 ng/ml) and HC (80.47±3.38 ng/ml). FAP levels at baseline correlated inversely with C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), interleukin (IL)-6, macrophage-associated protein YKL-40 (Chitinase 3-like 1/CHI3L1) levels and monocyte counts. Plasma FAP levels in GCA patients decreased even further at 3 months (37.23±2.10 ng/ml) upon glucocorticoid-induced remission, and gradually increased to the level of HC (76.84±5.43 ng/ml) when patients were in TFR. Increased FAP expression in GCA TAB (adventitia, media, intima) and aorta (media) compared with tissues from non-GCA was documented. FAP was abundantly expressed in fibroblast- and macrophage-rich areas but not in VSMC-rich areas in TAB and aorta of GCA patients. Conclusion FAP expression is clearly modulated both in plasma and at the site of vascular inflammation in GCA and may represent a pathogenic link between the inflammatory and remodeling processes in GCA. As such, FAP may have utility as a biomarker and should be further investigated as target for therapeutic intervention. References [1]Parreau Simon VN, Regent Alexis, et al. (2019). Adventitial fibroblast, an important player in giant cell arteritis. Annual European Congress of Rheumatology, EULAR 2019: Annals of the Rheumatic Diseases), pp. 434.2-5. [2]Brokopp CE, Schoenauer R, Richards P, et al. Fibroblast activation protein is induced by inflammation and degrades type I collagen in thin-cap fibroatheromata. Eur Heart J. 2011; 32: 2713-22. [3]Croft AP, Campos J, Jansen K, et al. Distinct fibroblast subsets drive inflammation and damage in arthritis. Nature. 2019; 570: 246-51. Acknowledgements No. Disclosure of Interests None declared